Sajid Shahul

Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator–activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy.

Mediators of cardiac injury in preeclampsia are not well understood. Preeclamptic women have decreased cardiac global longitudinal strain (GLS), a sensitive measure of systolic function that indicates fibrosis and tissue injury. GLS is worse in preeclampsia compared to gestational hypertension, despite comparable blood pressure, suggesting that placental factors may be involved. We previously showed that Activin A, a pro-fibrotic factor produced in excess by the placenta in preeclampsia, predicts impaired GLS postpartum. Here, we hypothesized that chronic excess levels of Activin A during pregnancy induces cardiac dysfunction. Rats were assigned to sham or activin A infusion (1.25–6 µg/day) on a gestational day (GD) 14 (n = 6–10/group). All animals underwent blood pressure measurement and comprehensive echocardiography followed by euthanasia and the collection of tissue samples on GD 19. Increased circulating activin A (sham: 0.59 ± 0.05 ng/mL, 6 µg/day: 2.8 ± 0.41 ng/mL, p < 0.01) was associated with impaired GLS (Sham: −22.1 ± 0.8%, 6 µg/day: −14.7 ± 1.14%, p < 0.01). Activin A infusion (6 µg/day) increased beta-myosin heavy chain expression in heart tissue, indicating cardiac injury. In summary, our findings indicate that increasing levels of activin A during pregnancy induces cardiac dysfunction and supports the concept that activin A may serve as a possible mediator of PE-induced cardiac dysfunction.

As intensivists with experience managing patients with coronavirus disease COVID-19 respiratory failure, we read with interest the article by Wong et al.1 describing risk factors for successful emergency airway management in COVID-19 patients. We applaud the impressive size, completeness, and multinational breadth of the dataset compiled by the authors.We recognize that first-pass success is an important metric for airway management and that COVID patients are challenging, in part due to precautions against disease transmission.2 However, we note that successful intubation may not fully describe the risk involved in difficult airway management, and that even when airway management is ultimately successful, physiologic derangements during the intubation process can be common.3Patients with COVID-19 may be particularly at risk for physiologic deterioration during airway management. In our hospital we found that aggressive use of noninvasive ventilation allowed many patients to avoid intubation.4 However, those who failed noninvasive ventilation were often exhausted after days of progressive respiratory insufficiency despite maximal use of high-flow nasal cannula, bilevel positive airway pressure, or helmet ventilation. Further, hypovolemia was common due to diuretic therapy to improve oxygenation. In such patients the combination of anesthetic induction, brief apnea, and transition to positive pressure ventilation often resulted in severe refractory hypoxemia and hypotension. Toward the end of our first wave (May 2020), we would not infrequently perform awake fiberoptic intubation in patients failing high-flow nasal cannula to avoid severe cardiorespiratory deterioration associated with even brief apnea and anesthetic induction.Wong et al. note that their registry did not capture the incidence or severity of hypoxemia or cardiovascular collapse due to airway management. Although we agree that hypoxemia and cardiovascular instability are not normally consequences of airway management, they may complicate physiologically difficult intubation5 and many COVID patients who fail noninvasive ventilation due to progressive disease fall into that category. Existing evidence suggests that first-pass success may not distinguish between anatomical and physiologically difficult airways,6 further limiting the ability of the first-pass success metric to detect cardiorespiratory consequences of COVID-19 airway management.Wong et al. describe a higher likelihood of first-pass success with rapid sequence intubation. It is unclear, however, whether this finding should be generalized to all patients with COVID-19 respiratory failure. Rapid sequence intubation may be well tolerated early in the course of COVID respiratory failure but markedly less well in those who require intubation after a week of failed noninvasive support. In such late-stage patients, airway managers should integrate physiologic complications of airway management into their decision tree.Dr. Tung receives a salary as Critical Care executive section editor for Anesthesia & Analgesia. Dr. Shahul is supported in part by National Institutes of Health (Bethesda, Maryland) grants R01HL148191 and R21HL14848811. Dr. Rubin is the president of DRDR Mobile Health (Chicago, Illinois), a company that creates mobile applications for healthcare, including functional capacity assessment applications. He has engaged in consulting for mobile applications as well. He has not taken any salary or money from the company.

Patients with a history of hypertensive disorders of pregnancy (HDP) suffer higher rates of long-term cardiovascular events including heart failure, coronary artery disease, and stroke. Cardiovascular changes during pregnancy can act as a natural stress test, subsequently unmasking latent cardiovascular disease in the form of HDP. Because HDP now affect 10% of pregnancies in the United States, the American Heart Association has called for physicians who provide peripartum care to promote early identification and cardiovascular risk reduction. In this review, we discuss the epidemiology, pathophysiology, and outcomes of HDP-associated cardiovascular disease. In addition, we propose a multi-pronged approach to support cardiovascular risk reduction for women with a history of HDP. Additional research is warranted to define appropriate blood pressure targets in the postpartum period, optimize the use of pregnancy history in risk stratification tools, and clarify the effectiveness of preventive interventions. The highest rates of HDP are in populations with poor access to resources and quality health care, making it a major risk for inequity of care. Interventions to decrease long-term cardiovascular disease risk in women following HDP must also target disparity reduction.

Background: Preeclampsia is a prominent risk factor for long‐term development of cardiovascular disease. Although existing studies report a strong correlation between preeclampsia and heart failure, the underlying mechanisms are poorly understood. One possibility is the glycoprotein growth factor activin A. During pregnancy, elevated activin A levels are associated with impaired cardiac global longitudinal strain at 1 year, but whether these changes persist beyond 1 year is not known. We hypothesized that activin A levels would remain increased more than 1 year after a preeclamptic pregnancy and correlate with impaired cardiac function. Methods and Results: To test our hypothesis, we performed echocardiograms and measured activin A levels in women approximately 10 years after an uncomplicated pregnancy (n=25) or a pregnancy complicated by preeclampsia (n=21). Compared with women with a previously normal pregnancy, women with preeclampsia had worse global longitudinal strain (−18.3% versus −21.3%, P =0.001), left ventricular posterior wall thickness (0.91 mm versus 0.80 mm, P =0.003), and interventricular septal thickness (0.96 mm versus 0.81 mm, P =0.0002). Women with preeclampsia also had higher levels of activin A (0.52 versus 0.37 ng/mL, P =0.02) and activin/follistatin‐like 3 ratio (0.03 versus 0.02, P =0.04). In a multivariable model, the relationship between activin A levels and worsening global longitudinal strain persisted after adjusting for age at enrollment, mean arterial pressure, race, and body mass index ( P =0.003). Conclusions: Our findings suggest that both activin A levels and global longitudinal strain are elevated 10 years after a pregnancy complicated by preeclampsia. Future studies are needed to better understand the relationship between preeclampsia, activin A, and long‐term cardiac function.

Background: Approximately 60% of women have Stage B heart failure 1 year after a preeclamptic delivery. Emerging evidence suggests that the profibrotic growth factor activin A, which has been shown to induce cardiac fibrosis and hypertrophy, is elevated in preeclampsia and may be inhibited by aspirin therapy. We hypothesized that preeclamptic women receiving aspirin would have lower activin A levels and reduced global longitudinal strain ( GLS ), a sensitive measure of cardiac dysfunction, than women who do not receive aspirin. To test our hypothesis, we performed a cohort study of women with preeclampsia or superimposed preeclampsia and compared activin A levels and GLS in parturients who did or did not receive aspirin. Methods and Results: Ninety‐two parturients were enrolled, of whom 25 (27%) received aspirin (81 mg/day) therapy. GLS , plasma activin A, and follistatin, which inactivates activin A, were measured. Women receiving aspirin therapy had lower median (interquartile range) levels of activin A (8.17 [3.70, 10.36] versus 12.77 [8.37, 31.25] ng/mL; P =0.001) and lower activin/follistatin ratio (0.59 [0.31, 0.93] versus 1.01 [0.64, 2.60] P =0.002) than women who did not receive aspirin, which also remained significant after multivariable analysis. Furthermore, GLS was worse in patients who did not receive aspirin (−19.84±2.50 versus −17.77±2.60%; P =0.03) despite no differences in blood pressure between groups. Conclusions: Our study suggests that antepartum aspirin therapy reduced serum activin A levels and improved GLS in preeclamptic patients, suggesting that aspirin may mitigate the postpartum cardiac dysfunction seen in women with preeclampsia.